This invention relates to hydroxamic acid derivatives, and to their use in medicine.
Metalloproteinases, including matrix metalloproteinase (MMP), collagenase, gelatinase and TNFxcex1 convertase (TACE), and their modes of action, and also inhibitors thereof and their clinical effects, are described in WO-A-96/11209, WO-A-97/12902 and WO-A-97/19075, the contents of which are incorporated herein by reference. MMP inhibitors may also be useful in the inhibition of other mammalian metalloproteinases such as the ADAM or ADAM-TS families. Members of the ADAM family include TNFxcex1 convertase (TACE) and ADAM-10, which can cause the release of TNFxcex1 from cells, and others, which have been demonstrated to be expressed by human articular cartilage cells and are also involved in the destruction of myelin basic protein, a phenomenon associated with multiple sclerosis.
The invention encompasses novel compounds of formula (I) which are inhibitors of matrix metalloproteinase, ADAM or ADAM-TS enzymes, and which are useful for the treatment of diseases mediated by those enzymes, including degenerative diseases and certain cancers.
Novel compounds according to a first aspect of the invention are represented by formula (I): 
wherein
R2 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or cycloalkyl (any of which may be optionally substituted with one or more substituents selected from R4, W and WR4);
R3 is a hydrogen atom or an alkyl group;
or R2, R3 and the carbon atom to which they are attached together represent a carbocylic or heterocyclic ring (either of which may be substituted with one or more substituents chosen from R4, W or WR4);
A is a heterocylic ring (attached to SO2 through a nitrogen atom) optionally substituted with R4;
B is an aryl or heteroaryl ring, optionally substituted with one or more R5;
D is an aryl or heteroaryl ring, optionally substituted with one or more R5; or a heterocyclic ring (attached through a carbon atom) optionally substituted with R4 at any available carbon atom or with R14 at any available nitrogen atom;
provided that both B and D are both not phenyl;
R4 is OR6, COR10, CO2R9, CONR7R8, NR10R11, S(O)qR10, S(O)qNR7R8, CN, xe2x95x90O or xe2x95x90NOR10, provided that R4 is not xe2x95x90O or xe2x95x90NOR10 if a substituent on an aromatic ring;
R5 is alkyl, cycloalkyl, CF3, OR6, COR10, S(O)qR10, CO2R9, CONR7R8, S(O)qNR7R8, halogen, NR10R11 or CN;
R6 is H, alkyl, CF3, CHF2, CH2F, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
R7 and R8, which may be the same or different, are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl, or R7 and R8 and the nitrogen to which they are attached together represent a heterocyclic ring;
R9 is H, alkyl or cycloalkyl;
R10 is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
R11 is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR12, CONR7R8, S(O)qR12 or S(O)qNR7R8, or R10 and R11 and the nitrogen to which they are attached together represent a heterocyclic ring optionally substituted by R13;
R12 is OR6 or R13;
R13 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl;
R14 is a hydrogen atom, alkyl or cycloalkyl;
q is 0, 1 or 2;
W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo, heterocycloalkyl and
X is xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, S(O)qxe2x80x94, xe2x80x94N(R10)xe2x80x94, or is absent;
and the salts, solvates, hydrates, N-oxides, protected amino, protected carboxy and protected hydroxamic acid derivatives thereof.
It will be appreciated that the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centres in a compound of formula (I) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.
It will further be appreciated that the compounds according to the invention may contain an oxime. This oxime can give rise to geometrical isomers, and in each case the invention is to be understood to extend to all such isomers and mixtures thereof.
As used in this specification, alone or in combination, the term xe2x80x9calkylxe2x80x9d refers to straight or branched chain alkyl moiety having from one to six carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.
The term xe2x80x9calkenylxe2x80x9d refers to a straight or branched chain alkyl moiety having two to six carbon atoms and having in addition one double bond, of either E or Z stereochemistry where applicable. The term alkenyl includes for example, vinyl, 1-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl and the like.
The term xe2x80x9calkynylxe2x80x9d refers to a straight or branched chain alkyl moiety having two to six carbon atoms and having in addition one triple bond. The term alkynyl includes for example, ethynyl, 1-propynyl, 1- and 2- butynyl, 1- methyl-2-butynyl and the like.
Cycloalkyl or carbocyclic ring refers to a non-aromatic cyclic or multicyclic, saturated or partially saturated ring system having from three to ten carbon atoms which may be optionally benzofused at any available position. Thus cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydronaphthyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]heptenyl, cyclopentenyl, indanyl and the like.
Heterocyclo or heterocyclic ring refers to a 3 to 10 membered saturated or partially saturated monocyclic or saturated or partially saturated multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur (or oxidised versions thereof, such as N-oxide, sulphoxide, sulphone). Examples include azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, quinuclidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, N-alkyl piperazinyl, such as N-methylpiperazinyl, homopiperazinyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, benzodioxolyl, [2,3-dihydro]benzofuryl, [3,4-dihydro]benzopyranyl, 1,2,3,4 tetrahydroquinolinyl, 1,2,3,4 tetrahydroisoquinolinyl, 8-oxabicyclo[3.2.1]octanyl, indolinyl, isoindolinyl, and the like.
For the case where A represents a heterocyclic ring, the heterocyclic moiety must contain at least one nitrogen atom. This includes, for example, azetidinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4 tetrahydroisoquinolinyl and the like.
Aryl indicates carbocyclic radicals containing 6 to 10 carbon atoms and containing either a single ring or two condensed rings. Thus aryl includes, for example, phenyl and naphthyl.
Heteroaryl refers to a 5 to 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur (or oxidised versions thereof, such as N-oxide). In general, the heteroaryl groups may be for example monocyclic or bicyclic fused ring heteroaryl groups. Monocyclic heteroaryl groups include, for example, five- or six-membered heteroaryl groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaryl groups include for example eight- to ten-membered fused-ring heteroaryl groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
The term heteroaryl includes, for example, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, benzothienyl, benzotriazolyl, indolyl, isoindolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzopyranyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]-pyridyl, quinolinyl, isoquinolinyl, phthalazinyl, tetrazolyl and the like.
Arylalkyl includes an aryl-alkyl- group wherein the aryl and alkyl are as described herein. Heteroarylalkyl includes a heteroaryl-alkyl-group, cycloalkylalkyl includes a cycloalkyl-alkyl-group and heterocycloalkyl includes a heterocyclo-alkyl-group, wherein all groups are as defined above.
The term xe2x80x9chalogenxe2x80x9d includes fluorine, chlorine, bromine or iodine.
The term xe2x80x9coptionally substitutedxe2x80x9d means optionally substituted by one or more of the groups specified, at any available position or positions.
The term xe2x80x9cbenzofusedxe2x80x9d means the addition of a benzene ring sharing a common bond with the defined ring system.
The terms xe2x80x9cprotected aminoxe2x80x9d, xe2x80x9cprotected carboxyxe2x80x9d and xe2x80x9cprotected hydroxamic acidxe2x80x9d mean amino, carboxy and hydroxamic acid groups which can be protected in a manner familiar to those skilled in the art. For example, an amino group can be protected by a benzyloxycarbonyl, tert-butoxycarbonyl, acetyl or like group, or may be in the form of a phthalimido or like group. A carboxyl group can be protected in the form of a readily-cleavable ester such as the methyl, ethyl, benzyl or tert-butyl ester. A hydroxamic acid may be protected as either N or O-substituted derivatives, such as O-benzyl or O-tert-butyldimethylsilyl.
Salts of compounds of formula (I) include pharmaceutically-acceptable salts, for example acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, p-toluenesulphonates, phosphates, sulphates, perchlorates, acetates, trifluoroacetates, propionates, citrates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts may also be formed with bases. Such salts include salts derived from inorganic or organic bases, for example alkali metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
When the xe2x80x9cprotected carboxyxe2x80x9d group in compounds of the invention is an esterified carboxyl group, it may be a metabolically-labile ester of formula CO2R where R may be an ethyl, benzyl, phenethyl, phenylpropyl, xcex1 or xcex2-naphthyl, 2,4-dimethylphenyl, 4-tert-butylphenyl, 2,2,2-trifluoroethyl, 1-(benzyloxy)benzyl, 1-(benzyloxy)ethyl, 2-methyl-1-propionyloxypropyl, 2,4,6-trimethylbenzyloxymethyl or pivaloylmethyl group.
In one group of compounds of formula (I), R14 is H.
In another group of compounds of the invention, R2 is H, alkyl, alkenyl, alkynyl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, cycloalkyl (any of which may be optionally substituted with one or more substituents selected from R4, W or WR4); R3 is a hydrogen atom or an alkyl group; or R2, R3 and the carbon atom to which they are attached together represent a carbocylic or heterocyclic ring (either of which may be substituted with one or more substituents chosen from R4, W or WR4).
In compounds of the invention, R2 may be an optionally substituted C1-6 alkyl group, particularly a C1-6 alkyl group. In compounds of this type, R2 is especially an isopropyl or isobutyl group, particularly an isopropyl group.
R3 in compounds of the invention may in particular be a hydrogen atom.
One group of compounds of the invention has the formula (I) in which R2, R3 and the carbon atom to which they are attached together represent an optionally substituted carbocylic or heterocyclic ring. Especially preferred compounds in this group are those where CR2R3 is cycloalkyl or a heterocyclic ring, in particular, C3-7 cycloalkyl groups, especially cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, and C3-7 heterocyclo groups, especially azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl and piperazinyl. In compounds of this type CR2R3 is especially cyclobutyl, cyclopentyl, cyclohexyl or in particular tetrahydropyranyl.
In another group of compounds of formula (I) A may in particular be a saturated monocyclic ring system containing at least one nitrogen atom, in particular, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and homopiperazinyl. Especially preferred groups include piperidinyl and piperazinyl.
X in compounds of formula (I) is preferably xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, or is absent, in particular X is xe2x80x94Oxe2x80x94 or is absent.
In one preferred group of compounds of formula (I) B is an optionally substituted aryl group and D is an optionally substituted heteroaryl or heterocyclic ring. One preferred group is where B is optionally substituted aryl and D is optionally substituted heteroaryl. More preferred is where B is optionally substituted phenyl and D is an optionally substituted monocyclic heteroaryl ring particularly pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl. Especially preferred is where B is optionally substituted phenyl and D is optionally substituted furyl, thienyl or pyridyl. Particular examples of R5 substituents, which may be present on these B and D groups, are CF3, OR6, CONR7R8, halogen and CN, in particular, CF3, OCH3, OCF3, OCHF2, OCH2F, CONH2, CONHCH3, CON(CH3)2, halogen and CN, particularly F, Cl, CN and CF3 groups.
In another preferred group of compounds of formula (I) B is optionally substituted heteroaryl and D is optionally substituted aryl, heteroaryl or heterocyclic ring.
One preferred class of compounds of this type is where B is optionally substituted heteroaryl and D is optionally substituted aryl. Particularly preferred is where B is an optionally substituted 6-membered heteroaryl ring containing at least one nitrogen atom and D is optionally substituted phenyl, in particular, B is optionally substituted pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, especially optionally substituted pyrimidinyl or pyridyl. Particular examples of R5 substituents, which may be present on these B and D groups, are CF3, OR6, CONR7R8, halogen and CN, in particular, CF3, OCH3, OCF3, OCHF2, OCH2F, CONH2, CONHCH3, CON(CH3)2, halogen and CN, particularly F, Cl, CN or CF3 groups.
A further group of compounds of the invention has the formula (I) in which each of B and D is optionally substituted heteroaryl. One preferred group is where each of B and D is optionally substituted pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl. Particular examples of R5 substituents, which may be present on these B and D groups, are CF3, OR6, CONR7R8, halogen and CN, in particular, CF3, OCH3, OCF3, OCHF2, OCH2F, CONH2, CONHCH3, CON(CH3)2, halogen and CN, particularly F, Cl, CN or CF3 groups.
A particular group of compounds of the invention has the formula (I) where R2 is C1-6 alkyl, especially isopropyl and R3 is H, or R2, R3 and the carbon atom to which they are attached is a C3-7 cycloalkyl or a C3-7 heterocyclic ring, especially, cyclobutyl, cyclopentyl, cyclohexyl or tetrahydropyranyl; X is absent; A is piperazinyl; B is optionally substituted aryl and D is optionally substituted heteroaryl. In compounds of this type B is especially optionally substituted phenyl and D is optionally substituted monocyclic heteroaryl. Especially preferred is where B is optionally substituted phenyl and D is optionally substituted furyl, thienyl or pyridyl. Particular examples of R5 substituents, which may be present on these B and D groups, are CF3, OR6, CONR7R8, halogen and CN, in particular, CF3, OCH3, OCF3, OCHF2, OCH2F; CONH2, CONHCH3, CON(CH3)2, halogen and CN, particularly F, Cl, CN or CF3 groups.
Another particular group of compounds of the invention is where R2 is C1-6 alkyl, especially isopropyl and R3 is H, or R2, R3 and the carbon atom to which they are attached is a C3-7 cycloalkyl or a C3-7 heterocyclic ring, especially, cyclobutyl, cyclopentyl, cyclohexyl or tetrahydropyranyl; X is absent; A is piperazinyl; B is optionally substituted heteroaryl and D is optionally substituted aryl. Particularly preferred is where B is an optionally substituted 6-membered heteroaryl ring containing at least one nitrogen atom and D is optionally substituted phenyl, in particular, B is optionally substituted pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, particularly optionally substituted pyridyl or pyrimidinyl. Particular examples of R5 substituents, which may be present on these B and D groups, are CF3, OR6, CONR7R8, halogen and CN, in particular, CF3, OCH3, OCF3, OCHF2, OCH2F, CONH2, CONHCH3, CON(CH3)2, halogen and CN, particularly F, Cl, CN or CF3 groups.
Another particular group of compounds of the invention is where R2 is C1-6 alkyl, especially isopropyl and R3 is H, or R2, R3 and the carbon atom to which they are attached is a C3-7 cycloalkyl or a C3-7 heterocyclic ring, especially, cyclobutyl, cyclopentyl, cyclohexyl or tetrahydropyranyl, particularly, tetrahydropyranyl; X is absent; A is piperazinyl; and each of B and D is optionally substituted heteroaryl, especially, optionally substituted pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl. Particular examples of R5 substituents, which may be present on these B and D groups, are CF3, OR6, CONR7R8, halogen and CN, in particular, CF3, OCH3, OCF3, OCHF2, OCH2F, CONH2, CONHCH3, CON(CH3)2, halogen and CN, particularly F, Cl, CN or CF3 groups. Particularly preferred compounds from this group are when R2 is isopropyl.
Another particular group of compounds of the invention is where R2 is C1-6 alkyl, especially isopropyl and R3 is H, or R2, R3 and the carbon atom to which they are attached is a C3-7 cycloalkyl or a C3-7 heterocyclic ring, especially, cyclobutyl, cyclopentyl, cyclohexyl and tetrahydropyranyl; X is absent or xe2x80x94Oxe2x80x94; A is piperidinyl; B is optionally substituted heteroaryl and D is optionally substituted aryl. Particularly preferred is where B is an optionally substituted 6-membered heteroaryl ring containing at least one nitrogen atom and D is optionally substituted phenyl, in particular, B is optionally substituted pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, particularly optionally substituted pyridyl. Particular examples of R5 substituents, which may be present on these B and D groups, are CF3, OR6, CONR7R8, halogen and CN, in particular, CF3, OCH3, OCF3, OCHF2, OCH2F, CONH2, CONHCH3, CON(CH3)2, halogen and CN, particularly F, Cl, CN or CF3 groups. Particularly preferred compounds from this group are when R2 is isopropyl.
An especially preferred class of compounds of the invention has the formula (I) where B is an optionally substituted pyrimidinyl group. D in compounds of this type is especially an optionally substituted phenyl, pyridyl, pyridazinyl or pyrazinyl group, especially an optionally substituted phenyl group. Particular examples of R5 substituents, which may be present, preferably as mono- or di-substituents, on D, are CF3, OR6, CONR7R8, halogen and CN, in particular, CF3, OCH3, OCF3, OCHF2, OCH2F, CONH2, CONHCH3, CON(CH3)2, halogen and CN, particularly F or Cl atoms. X in compounds of this type is especially xe2x80x94Oxe2x80x94 or is absent; most preferably, X is absent. In compounds of this class A is preferably a piperazinyl or piperidinyl ring, especially a piperazinyl ring. A particularly preferred group of compounds of this class is where R2 is C1-6 alkyl, especially isopropyl and R3 is H, or R2, R3 and the carbon atom to which they are attached is a C3-7 cycloalkyl or a C3-7 heterocyclic ring, especially, cyclobutyl, cyclopentyl, cyclohexyl or tetrahydropyranyl. Especially preferred is where R2 is isopropyl and R3 is H.
Particularly preferred compounds of the invention are:
2-[4-(4-Furan-2-yl-phenyl)piperazine-1-sulfonylmethyl]-N-hydroxy-3-methyl butyramide;
2-[4-(4-Pyridin-3-yl-phenyl)piperazine-1-sulfonyl methyl]-N-hydroxy-3-methyl butyramide;
4-[4-(4-Thiophen-2-yl-phenyl)piperazine-1-sulfonylmethyl]-tetrahydropyran-4-carboxylic acid-N-hydroxyamide;
4-[4-(4-Pyridin-3-yl-phenyl)piperazine-1-sulfonylmethyl]-tetrahydropyran-4-carboxylic acid-N-hydroxyamide;
4-[4-(4-Furan-2-ylphenyl)piperazine-1-sulfonylmethyl]-tetrahydropyran-4-carboxylic acid-N-hydroxyamide;
2-(R)-{4-[5-(4-Chlorophenyl)pyridin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide;
2-(R)-{4-[5-(4-Fluorophenyl)pyridin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide;
4-{4-[5-(4-Fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl} tetrahydropyran-4-carboxylic acid-N-hydroxyamide;
2-{4-[5-(4-Fluorophenyl)pyridin-2-yloxy]piperidine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide;
2-(R)-[4-(5-pyridin-3-yl-pyriridin-2-yl)piperazine-1-sulfonylmethyl]-N-hydroxy-3-methylbutyramide;
2-(R)-{4-[5-(4-cyanophenyl)pryimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide;
2-(R)-{4-[5-(3,4-dichlorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide;
2-(R)-{4-[5-(4-trifluoromethylphenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide;
1-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}cyclohexanecarboxylic acid-N-hydroxyamide;
2-(R)-{4-[5-(4-chlorophenyl)pyrimidin-2-yl]piperidine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide;
2-(R)-{4-[5-(4-Fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide;
and the salts, solvates, hydrates, N-oxides, protected amino, protected carboxy and protected hydroxamic acid derivatives thereof.
Compounds of the general formula (I) may be prepared by any suitable method known in the art and/or by the following processes.
It will be appreciated that, where a particular stereoisomer of formula (I) is required, the synthetic processes described herein may be used with the appropriate homochiral starting material and/or isomers maybe resolved from mixtures using conventional separation techniques (e.g. HPLC).
The compounds according to the invention may be prepared by the following process. In the description and formulae below, the various groups R and other variables are as defined above, except where otherwise indicated. It will be appreciated that functional groups, such as amino, hydroxyl or carboxyl groups, present in the various compounds described below, and which it is desired to retain, may need to be in protected form before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction scheme. Suitable protecting groups for such functionality will be apparent to those skilled in the art. For specific details see Greene et al, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Wiley Interscience.
Compounds of formula (I) may be prepared according to the routes depicted in the Scheme below. An acid of formula (ii) (in which B incorporates an appropriate substituent such as halogen or triflate) may be converted into a compound of formula (iv) in which R1 represents OH using any suitable procedure known to those skilled in the art. Suitable procedures include the use of a palladium catalysed biaryl coupling procedure. Such procedures may be carried out using, for example, an appropriate boronic acid, tetrachloropalladate, diphenylphosphinobenzene-3-sulfonic acid sodium salt and a suitable base in an appropriate solvent, such as aqueous ethanol. Advantageously, the reaction may be carried out at elevated temperature, such as at 80xc2x0 C. Compounds of formula (iv) may be converted into compounds of formula (I) using any standard procedure known to those skilled in the art. Suitable procedures are described in WO-A-98/05635, for example.
For example, treatment of acids of formula (iv) with oxalyl chloride in an inert solvent (such as dichloromethane) gives an intermediate acid chloride, which may or may not be isolated, but which in turn is reacted with hydroxylamine at a suitable temperature such as room temperature to give the desired hydroxamic acids (I). Alternatively an acid of formula (iv) maybe activated in situ using for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, advantageously in the presence of a catalyst such as a N-hydroxy compound, e.g. N-hydroxybenzotriazole using suitable conditions, e.g. in N,N-dimethylformamide at xe2x88x9215xc2x0 C., prior to the subsequent addition of a suitably protected hydroxylamine such as tert-butyldimethylsilyl hydroxylamine and warming to ambient temperature. The protecting group maybe removed using appropriate conditions, such as water or tetrabutylammonium fluoride and acetic acid in tetrahydrofuran at 0xc2x0 C., to yield the desired hydroxamic acids of formula (I). Alternatively, compounds of formula (I) may be prepared from compounds of formula (iii) (in which B incorporates an appropriate substituent such as halogen or triflate) using any suitable procedures known to those skilled in the art, for example by using a palladium catalysed biaryl coupling. Such a coupling reaction may be achieved by employing an appropriate boronic acid, tetrakis(triphenylphosphine)palladium(0) and potassium phosphate in an appropriate solvent. Appropriate solvents include aqueous 1,2-dimethoxyethane, and the reaction may advantageously be carried out at elevated temperature, such as the reflux temperature of the solvent.
The hydroxamic acids of general formula (iii) may be prepared from the carboxylic acids of formula (ii) using the methods described herein. 
Compounds of formula (ii) and (iii) may be prepared using any suitable procedures known to those skilled in the art, particularly those procedures described in WO-A-98/05635 and WO-A-99/24399.
The compounds of general formula (iv) may be prepared using the following general reaction scheme as shown below: 
Carboxylic acids of general formula (iv) may be prepared by deprotection of a suitably protected carboxylic acid of formula (xi). For example, where W is an alkoxy group, such as methoxy or ethoxy, a base such as aqueous lithium hydroxide may be used, alternatively trifluoroacetic acid may be used when W is a tert-butoxy group or in the case of a chiral auxiliary such as 4-(R)-benzyl-oxazolidin-2-one, lithium hydroxide/hydrogen peroxide may be used. Appropriate solvent and temperature conditions such as those described in the examples hereinafter may be used.
Compounds of formula (xi), where W is for example an alkoxy group, such as methoxy, ethoxy or tert-butoxy or a chiral auxiliary, for example, 4-(R)-benzyl-oxazolidin-2-one, may be prepared by methods well known in the literature, for example, by reaction of a sulfonyl chloride (x) with an amine (ix) in the presence of an amine base, such as triethylamine in a halogenated solvent, such as dichloromethane at room temperature.
Compounds of general formula (x) are either known or may be made by one skilled in the art using conditions known in the literature, see for example WO-A-99/24399, or as described in the examples herein after. Amines of general formula (viii), where P is a suitable protecting group, such as a carbamate e.g. tert-butyl ester, may be deprotected using conditions well known in the literature to provide amines of formula (ix).
A compound of general formula (vii) (in which B incorporates an appropriate substituent such as a halogen or triflate) may be converted to a compound of formula (viii) using any suitable procedure known in the literature. Suitable procedures include the use of a palladium-catalysed biaryl coupling procedure. Such procedures may be carried out using, for example, an appropriate boronic acid, a catalyst such as, tetrakis(triphenylphosphine)palladium(0) in the presence of potassium phosphate. Appropriate solvents and conditions which may be used are described herein. Alternatively a compound of formula (viii) where A is a piperidine ring and P is a suitable protecting group, such as methyl, may be prepared by selective reduction of the corresponding N-methylated pyridine A-ring precursor. Suitable conditions may use a reducing agent such as sodium borohydride in an appropriate solvent, such as aqueous methanol to give a partially reduced ring, which may then be further reduced under a hydrogen atmosphere in the presence of an appropriate catalyst, such as platinum oxide. The methyl protecting group may be removed using for example 1-chloroethyl chloroformate followed by quenching with a suitable alcohol, such as methanol to give an amine of formula (ix). An appropriate solvent for this reaction may be dichloromethane.
When B or D in compounds of formula (viii) is a heteroaryl ring it may be made using standard ring formation methodology. For example, when B is a pyrimidine ring, it may be prepared by reaction of an appropriate amidine, e.g. isonicotinamidine, with an appropriate di-carbonyl compound, e.g. 2-(4-chlorophenyl)malonaldehyde, in a solvent such as refluxing pyridine. The compound obtained may require further conversion to give a compound of formula (viii), for example, by selective reduction of ring A using the methods described herein or by methods known to those skilled in the art.
A compound of formula (vii) may be prepared by suitably protecting an amine of formula (vi) (which may be commercially available, or readily made using procedures known to those skilled in the art) with for example, a carbamate, such as tert-butyl ester using standard conditions. Alternatively a compound of formula (vii) may be prepared by reaction of a compound of formula (v) with a suitable B group, for example, where B incorporates an appropriate substituent such as a halogen or triflate, using conditions as described herein or methods known to those skilled in the art.
Likewise compounds of general formula (ii) may be prepared in a similar manner by reaction of a compound of formula (vi) with a sulfonyl chloride of formula (x) using the conditions described herein.
Compounds of formula (I) may also be prepared by interconversion of other compounds of formula (I).
Similarly, intermediates of any appropriate formula may be prepared by the interconversion of other compounds of the same formula.
Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallization, or by formation of a salt if appropriate or possible under the circumstances.
Compounds according to the invention exhibit in vitro inhibiting activities with respect to the MMP enzymes, for example, stromelysin, collagenase, gelatinase or ADAM or ADAM-TS enzymes.
The activity and selectivity of the compounds may be determined by use of the appropriate enzyme inhibition test, for example as described in Examples A-M of WO-A-98/05635.
This invention also relates to a method of treatment for patients (including man and/or mammalian animals raised in the dairy, meat or fur industries or as pets) suffering from disorders or diseases which can be attributed to stromelysin as previously described, and more specifically, a method of treatment involving the administration of the matrix metalloproteinase inhibitors of formula (I) as the active constituents.
Accordingly, the compounds of formula (I) can be used among other things in the treatment of osteoarthritis and rheumatoid arthritis, and in diseases and indications resulting from the over-expression of these matrix metalloproteinases such as found in certain metastatic tumour cell lines, or conditions involving ocular neovascularisation.
As mentioned above, compounds of formula (I) are useful in human or veterinary medicine since they are active as inhibitors of MMPs. Accordingly in another aspect, this invention concerns:
a method of management (by which is meant treatment or prophylaxis) of disease or conditions mediated by MMPs in mammals, in particular in humans, which method comprises administering to the mammal an effective, amount of a compound of formula (I) above, or a pharmaceutically acceptable salt thereof; and
a compound of formula (I) for use in human or veterinary medicine, particularly in the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by MMPs; and
the use of a compound of formula (I) in the preparation of an agent for the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by MMPs.
The disease or conditions referred to above include inflammatory diseases, autoimmune diseases, cancer, cardiovascular diseases, diseases involving tissue breakdown. Appropriate diseases include rheumatoid arthritis, osteoarthritis, osteoporosis, neurodegeneration, Alzheimer""s disease, stroke, vasculitis, Crohn""s disease, ulcerative colitis, multiple sclerosis, periodontitis, gingivitis and those involving tissue breakdown such as bone resorption, haemorrhage, coagulation, acute phase response, cachexia and anorexia, acute infections, bacterial infections, HIV infections, fever, shock states, graft versus host reactions, dermatological conditions, surgical wound healing, psoriasis, atopic dermatitis, epidermolysis bullosa, tumour growth, angiogenesis and invasion by secondary metastases, ophthalmological disease, retinopathy, corneal ulceration, reperfusion injury, migraine, meningitis, asthma, rhinitis, allergic conjunctivitis, eczema, anaphylaxis, restenosis, congestive heart failure, endometriosis, atherosclerosis, endosclerosis, aspirin-independent anti-thrombosis, systemic lupus erythematosus and solid organ transplant.
Compounds of formula (I) may also be useful in the treatment of pelvic inflammatory disease (PID), and cancer-induced bone resorption. Further, they can be used in the treatment of lung diseases, e.g. selected from cystic fibrosis, adult respiratory distress syndrome (ARDS), emphysema, bronchitis obliterans-organising pneumonia (BOOP), idiopathic pulmonary fibrosis (PIF), diffuse alveolar damage, pulmonary Langerhan""s cell granulamatosis, pulmonary lymphangioleiomyomatosis (LAM) and chronic obstructive pulmonary disease (COPD).
Compounds of the invention are particularly of use in the treatment of inflammatory diseases, autoimmune diseases and cancer. Thus, for example, the compounds may be used in the treatment (including prophylaxis) of graft versus host reactions, psoriasis, atopic dermatitis, rhinitis, eczema, systemic lupus erythematosus, solid organ transplant, cystic fibrosis and especially rheumatoid arthritis, osteoarthritis, osteoporosis, Crohn""s Disease, ulcerative colitis, multiple sclerosis, periodontitis, bone resorption, bacterial infections, epidermolysis bullosa, tumour growth, angiogenesis, ophthalmological disease, retinopathy, asthma, emphysema, bronchitis, and chronic obstructive pulmonary disease (COPD).
The diseases or conditions involving ocular neovascularization, include, but are not limited to, diabetic retinopathy, chronic glaucoma, retinal detachment, retinopathy of prematurity (ROP), sickle cell retinopathy, age-related macular degeneration (ARMD), rubeosis iritis, central retinal vein occlusion, chronic uveitis, neoplasms (retinoblastoma, pseudoglioma), Fuch""s heterochromic iridocyclitis, Sorsby""s maculopathy, neovascular glaucoma, corneal neovascularization, neovascularization following a combined vitrectomy and lensectomy, retinal ischemia, choroidal vascular insufficiency, choroidal thrombosis, carotid artery ischemia, neovascularization of the optic nerve and neovascularization due to penetration of the eye or contusive ocular injury, such as traumatic disciform lesions. Of particular interest are ARMD, ROP and diabetic retinopathy, especially ARMD.
The compounds of formula (I) may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Ocular injection, such as intravitreal, subtenons, subconjunctival, periocular and retrobulbar may also be used, as well as intraocular slow release devices and implants. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats etc., the compounds of the invention are effective in the treatment of humans.
The pharmaceutical composition containing the active ingredient maybe in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. No. 4,256,108, U.S. Pat. No. 4,166,452 and U.S. Pat. No. 4,265,874, to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules where in the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavouring and colouring agents may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
A compound of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing a compound of the invention are employed. For the purposes of this specification, topical application includes mouthwashes and gargles.
For topical ocular administration pharmaceutically acceptable solutions, suspensions or gels containing the compounds of formula (I) may be used. Solutions and suspensions may also be adapted for intra-vitreal or intra-cameral use.
Dosage levels of the order of from about 0.05 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 2.5 mg to about 7 g per patient per day). For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 0.5 mg to about 3.5 g per patient per day).
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may vary from about 5 to about 95% of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of active ingredient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.